Lecture 3

Innate Immunity
Nothing in biology makes sense except in the light of evolution. - Theodosius Dobhansky
!ummary of Distribution of Immune "esponses
organism innate defenses (PRR,
attack peptides, and more)
phagocytosis transplant (graft)
rejection
adaptive defenses
(B and T cells)
plants yes no no no
sponges yes yes yes no
arthropods yes yes yes no
fish yes yes yes yes
reptiles yes yes yes yes
birds yes yes yes yes
mammals yes yes yes yes
I. Basic onsiderations! "n innate defense is one that yo# can prod#ce prior to e$pos#re by a
specific pathogen.
". %bi&#ity, Table '!(
(. Insects have amoeboid cells patrolling their body cavities and can make anti!bacterial
or anti!f#ngal peptides )hen challenged by specific pathogens.
*. Plants have an even )ider array of pathogen sensors than do mammals. They can
respond by prod#cing en+ymes, antimicrobial peptides and a )ide assortment of to$ic
compo#nds.
'. ,tem chordates, like the sea s&#irts (t#nicates) and "mphio$#s (lancelets), have
innate, b#t not adaptive, defenses. People st#dy them to get cl#es as to ho) adaptive
imm#nity might have evolved in the vertebrates.
B. "natomic Barriers. -ike other animals, mammals maintain a discrete bo#ndary bet)een
themselves and the o#tside )orld, and like other animals, constantly fend off the attempts
of pathogens to breach it.
(. ,kin (tertiary imm#ne organ). /e) pathogens can penetrate intact skin, relying
instead on bites and abrasions
a. 0pidermis (fig#re) thin layer of dead cells (keratin) over a thinner layer of live
regenerative cells over a basement membrane. 1land cells and hair follicles arise
here #nder instr#ction from lo)er layers, secreting seb#m (lipid mi$t#re), agents
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to adj#st the p2, and antibacterial peptides incl#ding psoriacin against E. coli.
b. 3ermis . deeper thicker layer )ith blood s#pply, connective tiss#e and
mesenchymal tiss#e important in developmental signaling.
*. 4#cosa. more v#lnerable, typically single layer of epithelial cells over basement
membrane over connective tiss#e, fig '!'
a. ,ecretions5 tears, m#c#s, lyso+yme.
b. ilia (l#ngs and reprod#ctive organs) s)eep o#t pathogens and debris trapped in
m#c#s
'. "dditional 1I defenses, fig '!(5
a. stomach acid (v#lt#re)
b. en+ymes
c. competing flora (good bacteria)
II. Inflammation
". /ever
(. 2ypothalam#s controls the body6s temperat#re set point.
*. /ever provides overt sign of imm#ne #p!reg#lation.
'. 2igher body temperat#re associated )ith better s#rvival rate, even in reptiles (t#rtle
pict#re)
7. /ever ind#ction #sed )ith mi$ed s#ccess to treat cancer at the t#rn of the *8
th
cent#ry
(ooley to$ins).
B. -ocal Response, fig#re '!9 . calls in phagocytic cells (and other defensive cells as )ell)
to the site of infection or inj#ry.
(. Recogni+ed in Roman times (heat, s)elling, pain, reddening and loss of f#nction).
*. ,ymptoms prod#ced by vasc#lar changes . capillaries become more permeable so
that plasma (edema) and cells (e$travasation) enter infected tiss#e.
'. -e#kocyte e$travasation (fig#re '!:, page ;8) is reg#lated by the changes in s#rface
"4 molec#les.
. ,ignals and Receptors5
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(. <hite cells and damaged tiss#es release chemokines, a type of cytokine, also
generally #p!reg#late inflammation, attracting cells to the site of the infection.
*. "ctivation of cells by pattern receptors also activates inflammatory signals and
interferon.
'. =e#trophils respond by changing the conformation of their integrins, )hich makes
them stick to the blood vessels near the problem, fig#re '!:, page ;8.
a. Rolling
b. "ctivation
c. "rrest
d. Transendothelial migration
7. The cytokines prod#ced may also reg#late the response so that it is most effective for
the partic#lar type of pathogen that initiated it.
9. "ctivated macrophages and dendritic cells then travel to the T
2
cells and present
antigen, specifically activating the adaptive response.
;. The T
2
cells then coordinate an adaptive attack on the infections.
III. Innate Targeting of Pathogens
". Revie)ing the Bad 1#ys
pathogen (xamples factoids )attern recognition alerted by*
>ir#ses /l#, small po$, 2I> an only
reprod#ce inside
cells
/oreign n#cleic acids (do#ble stranded
R=", single stranded 3=", foreign
methylation patterns), red#ced antigen
presentation by infected cells.
Bacteria ,trep, staph, TB,
anthra$, leprosy
Reprod#ce
intracell#larly or
e$tracell#larly,
depending on type
haracteristic s#rface carbohydrates
(peptidoglycan, #n!s#bstit#ted mannose),
flagellar proteins (flagellin), lipids
(lipotechoic acid) characteristic 3="
methylation patterns
/#ngi andida (thr#sh)
athlete6s foot
+ymosan, a !gl#can cell )all component
chitin . cell#lose )ith =!acetyl
gl#cosamine instead of j#st gl#cose
Proto+oa 4alaria, hagas,
sleeping sickness,
amebic dysentery,
leishmaniasis
%nicell#lar
e#karyotes
haracteristic cell s#rface proteins
(profilin) and lipids (glycosylated
phosphatidyl inositols ! 1PI)
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<orms
(helminth
parasites)
pin )orms, hook
)orms,
schistosomiasis,
fl#kes, tape)orms
Primarily
members of
Platyhelminthes
(flat)orms) and
=ematoda
(ro#nd)orms)
haracteristic cell s#rface proteins
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B. P"4Ps (Pathogen "ssociated 4olec#lar Patterns) Recogni+ed by PRRs . pattern
recognition receptors.
(. proteins ! ,o far, )e have identified very fe) proteins that )e recogni+e innately by
their overall str#ct#re. The ones )e6ve fo#nd are5
a. /lagellin (fig#re) . bacteria
b. profilin . s#rface protein of proto+oan (to$oplasmosis)
*. carbohydrates and glycopeptides, fig#re '!?
a. +ymosan . component of f#ngal cell )alls . a vag#e term beca#se it has not been
e$actly characteri+ed.
b. peptidoglycan . the cell )all component of both gram positive and gram negative
bacteria, altho#gh gram positive have a m#ch thicker )all.
'. lipids, especially attach to signat#re carbohydrates or peptides.
7. n#cleic acids
a. 3=" )ith specific methylation patterns ! recall restriction endon#cleases.
b. @)rong strandednessA . single stranded 3=" and do#ble stranded R=" are
#s#ally signs of a potential threat.
c. 4ice can specifically recogni+e the *'s component of bacterial ribosomes.
. ategories of PRRs (fig#re '!7, page 9;.) ,pecific receptors bind to characteristic
pathogen molec#les.
(. 0$tracell#lar
a. -yso+yme (m#c#s and tears) . against peptidoglycans
b. Psoriacin (skin) fig#re '.*, page 99. against E. coli. an be ind#ced by s#nlight
(%>B) via vitamin 3.
c. "4P, . defensive peptides that that typically kill by disr#pting bacterial
membranes.
d. 4annose!binding lectin (plasma) . activates complement.
e. !reactive protein (RP) (plasma) also recogni+es microbes and damaged self!
cells.
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f. -ipopolysaccharide binding protein (-BP) specifically recogni+es gram negative
bacteria.
*. cytoplasmic ! =B3 proteins (=#cleotide!binding oligomeri+ation domains) 3espite
the name, the best!kno)n =B3, =B3*, recogni+es bacterial cell )alls.
'. 4embrane Bo#nd . the Toll!like receptors (T-Rs), fig#res '!(8, page ;7 and '!((,
page ;7.
a. <ork singly or in pairs. ,ingles e$tend onto the endoplasmic retic#l#m l#men,
pairs from the plasma membrane.
b. Binding of a molec#le characteristic of a pathogen on the o#tside of the
membrane triggers a signal on the opposite side.
c. The internal signal activates =/!B, the major internal inflammation reg#lator.
d. =/!B (fig#re '!(7) t#rns on the prod#ction of cytokines, alerting a variety of
other imm#ne cells.
e. Identify the category of pathogen and set of inflammatory and adaptive response,
table on p ;7 )ith additions.
T-R recogni+es pathogen membrane
( Triacyl lipopeptides mycobacteria plasma
( C * Peptidoglycan component and
triacylated lipopeptides
lipotechoic acid
+ymosan (!gl#can cell )all
component)
m#cin
1ramD bacteria
mycobacteria
yeasts and f#ngi
trypanosomes
plasma
* C ; lipopeptides 1ramD bacteria and
mycoplasma
plasma
7 C 7 ()E
43*)
lipopolysaccharide (e$terior
membrane)
/!protein
bacteria =i (FG)
R,> vir#s
plasma
9 (C9F) /lagellin /lagellated bacteria plasma
; 3iacyl lipopeptides
+ymosan
4ycobacteria
Heasts and f#ngi
plasma
(8 (=on!
f#nctional
in mice)
#nkno)n allergens plasma
(( (mice
only)
Profilin 0#karyotic parasites
(also recogni+es bacteria)
plasma
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(* (mice
only)
profilin 0#karyotic parasites
(especially trypanosomes)
plasma
(' mice
only
bacterial *'sR=" prokaryotes endomembrane
' 3o#ble!stranded R=" vir#ses endomembrane
: ,ingle!stranded viral R=" vir#ses (2I>) endomembrane
I ,ingle!stranded viral R=" vir#ses endomembrane
? 3=" )ith #nmethylated p1
signat#res
vir#s and bacteria endomembrane
f. 4echanism for endomembrane T-Rs
g. =egative reg#lation! yo# have to be able to t#rn these off or yo# get e$cess
inflammation and maybe and a#toimm#ne disease.
h. Interact )ith5 43* at s#rface for binding -P, (and also certain viral and cancer
proteins), 4y3II to initiate internal signal se&#ence.
I>. ell Types and /#nction
". Phagocytosis . 4acrophages and =e#trophils . capt#re pathogens and kill them )ith a
comple$ to$ic bre).
(. apt#re pathogen in phagosome, promoted by P"4P, complement or antibody on
s#rface of pathogen. ! activates membrane p#mp )hich
*. Triggers respiratory b#rst (B
*
#ptake) by ="3P2 phagosome o$idase (pho$
en+ymes) comple$. This is not mitochondrial respiration, b#t rather the direct #ptake
of o$ygen by en+ymes that #se it to create to$ic reactive o$ygen species (RB,),
fig#re '!(', page ;I.
a. s#pero$ide radicals (B
*
.J
)
b. hydrogen pero$ide (2
*
B
*
)
c. 2B- (hypochloro#s acid or bleach)
'. ,#pero$ide radicals also generate reactive nitrogen species (R=,) incl#ding =B, also
to$ic
7. B$idation is co#pled to K
D
transport, rendering the interior hypertonic. K
D
enters to
compensate for the negative charges, res#lting in a rise in p2 (I.9). Bnce the p2
reaches this, f#rther ne#trali+ation is done by transporting 2
D
.
9. hange in K
D
and tonicity dispersed protein gran#les. These release
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a. hydrolytic en+ymes (different kinds, as bacteria have different sensitivities to
different versions).
b. peptides that poke holes in the bacterial plasma membrane (BPI or defensin)
;. 4icrofilaments package the e$terior of the vac#ole, preventing s)elling and
maintaining the concentration of to$ic compo#nds inside.
B. ells, fig#re '!(*, page ;9.
(. =e#trophils ! the infantry in the modern sense, and the first on!site defenders.
*. 4acrophages ! the cavalry of the o#tfit. Phagocytosis ca#ses them to secrete I-!(,
I-!; and T=/L, all inflammation activators.
'. 3endritic cells ! the sco#ts and patrols. 4ost important initial trigger of the adaptive
response. They phagocyti+e primarily in order to sample pathogens and activate
inflammation on the adaptive response.
7. =K ells ! f#nction by pattern recognition making them part of innate defenses.
Principally attack rog#e!self by ind#cing apoptosis.
>. ,#mmary
". ompare and ontrast Innate and "daptive Imm#nity
Innate and #daptive Immunity /ompared
/haracteristic Innate #daptive
speed response 0ithin minutes first response* ' 0eeks
second response* 3 days
recognies molecules characteristic of non-self most proteins% many
carbohydrates and a fe0 lipids
diversity hundreds of types% soluble and
membrane bound
1#!T number of types%
soluble and membrane bound
gene rearrangement
needed
no yes
may attack self no yes
memory no yes% prior exposure speeds
response.
/ells myeloid cells% especially
phagocytes% N2 cells
3lymphocytes4
5 cells% T cells 3instructed by
myeloid antigen-presenting
cells4
found in all living organisms 3in various
forms4
vertebrates only
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B. Innate 0$amples
secretions across
skin
secretion across
m#c#s
membranes
plasma,
interstitial fl#id
cell membranes cell cytoplasm
(l#men of
endomembrane
system)
seb#m m#c#s complement
(4B-), -BP
T-Rs =B3*,
defensins,
hydrolytic
en+ymes
antimicrobial
peptides
(psoriacin and
cathelicidin)
lyso+yme
(hydrolytic
en+yme attacking
peptidoglycan)
defensins
!reactive
protein (bind
microbial
s#rfaces)
RB,E R=,
p2 adj#stment
(slightly acid)
acids (slight to
strong)
p2 adj#stment
(basic)
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